Cyclic sulfone derivatives

Abstract

A compound of the formula ##STR1## wherein n, X, Y and Ar are as defined herein, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID'S) and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.

We claim: 
     
       1. A compound of the formula ##STR6## or a pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond; n is 0, 1 and 2;   X and Y are each independently CR 1  wherein R 1  is hydrogen, (C 1  -C 6 )alkyl optionally substituted by (C 1  -C 6 )alkylamino, (C 1  -C 6 )alkylthio, (C 1  -C 6 )alkoxy, trifluoromethyl, (C 6  -C 10 )aryl, (C 5  -C 9 )heteroaryl, (C 6  -C 10 )arylamino, (C 6  -C 10 )arylthio, (C 6  -C 10 )aryloxy, (C 5  -C 9 )heteroarylamino, (C 5  -C 9 )heteroarylthio, (C 5  -C 9 )heteroaryloxy, (C 6  -C 10 )aryl(C 6  -C 10 )aryl, (C 3  -C 6 )cycloalkyl, hydroxy(C 1  -C 6 )alkyl, (C 1  -C 6 )alkyl(hydroxymethylene),piperazinyl,(C 6  -C 10 )aryl(C 1  -C 6 )alkoxy,(C 5  -C 9 )heteroaryl(C 1  -C 6 )alkoxy, (C 1  -C 6 )acylamino, (C 1  -C 6 )acylthio, (C 1  -C 6 )acyloxy, (C 1  -C 6 )alkylsulfinyl, (C 6  -C 10 )arylsulfinyl, (C 1  -C 6 )alkylsulfonyl, (C 6  -C 10 )arylsulfonyl, amino, (C 1  -C 6 )alkylamino or ((C 1  -C 6 )alkyl) 2  amino or R 1  is; trifluoromethyl, (C 1  -C 6 )alkyl (difluoromethylene), (C 1  C 3 )alkyl(difluoromethylene)(C 1  -C 3 )alkyl, (C 6  -C 10 ) aryl, (C 5  -C 9 )heteroaryl, (C 3  -C 6 )cycloalkyl, (C 1  -C 6 )alkyl-(hydroxymethylene), R 3  (C 1  -C 6 )alkyl wherein R 3  is (C 1  -C 6 )acylpiperazino, (C 6  -C 10 )arylpiperazino, (C 5  -C 9 )heteroarylpiperazino, (C 1  -C 6 )alkylpiperazino, (C 6  -C 10 )aryl(C 1  -C 6 )alkylpiperazino, (C 5  -C 9 )heteroaryl(C 1  -C 6 )alkylpiperazino, morpholino, thiomorpholino, pyrrolidino, piperidyl, (C 1  -C 6 )alkylpiperidyl, (C 6  -C 10 )arylpiperidyl, (C 5  -C 9 )heteroarylpiperidyl, (C 1  -C 6 )alkylpiperidyl(C 1  -C 6 )alkyl, (C 6  -C 10 )arylpiperidyl(C 1  -C 6 )alkyl, (C 5  -C 9 )heteroarylpiperidyl(C 1  -C 6 )alkyl or (C 1  -C 6 )acylpiperidyl;   or a group of the formula ##STR7## wherein r is 0 to 6; D is hydroxy, (C 1  -C 6 )alkoxy,piperidyl,(C 1  -C 6 )alkylpiperidyl,(C 6  -C 10 )arylpiperidyl, (C 5  -C 9 )heteroarylpiperidyl, (C 1  -C 6 )acylpiperidyl or NR 4  R 5  wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, (C 1  -C 6 )alkyl optionally substituted by (C 1  -C 6 )alkylpiperidyl, (C 6  -C 10 )arylpiperidyl, (C 5  -C 9 )heteroarylpiperidyl, (C 6  -C 10 )aryl, (C 5  -C 9 )heteroaryl, (C 6  -C 10 )aryl(C 6  -C 10 )aryl or (C 3  -C 6 )cycloalkyl; or R 4  and R 5  are each independent by selected from the group consisting of (C 6  -C 10 )aryl (C 5  -C 9 )heteroaryl, (C 6  -C 10 )aryl(C 6  -C 10 )aryl, (C 3  -C 6 )cycloalkyl, R 6  (C 2  -C 6 )alkyl, (C 1  -C 5 )alkyl(CHR 6 )(C 1  -C 6 )alkyl wherein R 4  is hydroxy, (C 1  -C 6 )acyloxy, (C 1  -C 6 )alkoxy, piperazino, (C 1  -C 6 )acylamino, (C 1  -C 6 )alkylthio, (C 6  -C 10 )arylthio, (C 1  -C 6 )alkylsulfinyl, (C 6  -C 10 )arylsulfinyl, (C 1  -C 6 )alkylsufonyl, (C 6  -C 10 )arylsulfonyl, amino, (C 1  -C 6 )alkylamino, ((C 1  -C 6 )alkyl) 2  amino, (C 1  -C 6 )acylpiperazino, (C 1  -C 6 )alkylpiperazino, (C 6  -C 10 )aryl(C 1  -C 6 )alkylpiperazino,(C 5  -C 9 )heteroaryl(C 1  -C 9 )heteroaryl(C 1  -C 6 )alkylpiperazino,morpholino,thiomorpholino, piperidino or pyrrolidino; or R 4  and R 5  are each independently selected from the group consisting of R 7  (C 1  -C 6 )alkyl, (C 1  -C 6 )alkyl(CHR 7 )(C 1  -C 6 )alkyl wherein R 7  is piperidyl or (C 1  -C 6 )alkylpiperidyl; or R 4  and R 5  is and CH(R 8 )COR 9  wherein R 8  is hydrogen, (C 1  -C 6 )alkyl, (C 6  -C 10 )aryl(C 1  -C 6 )alkyl, (C 5  -C 9 )heteroaryl(C 1  -C 6 )alkyl, (C 1  -C 6 )alkylthio(C 1  -C 6 )alkyl, (C 6  -C 10 )arylthio(C 1  -C 6 )alkyl, (C 1  -C 6 )alkylsulfinyl(C 1  -C 6 )alkyl, (C 6  -C 10 )arylsulfinyl(C 1  -C 6 )alkyl, (C 1  -C 6 )alkylsulfonyl(C 1  -C 6 )alkyl, (C 6  -C 10 )arylsulfonyl(C 1  -C 6 )alkyl, hydroxy(C 1  -C 6 )alkyl, amino(C 1  -C 6 )alkyl, (C 1  -C 6 )alkylamino(C 1  -C 6 )alkyl, ((C 1  -C 6 )alkylamino) 2  (C 1  -C 6 )alkyl, R 10  R 11  NCO(C 1  -C 6 )alkyl or R 10  OCO(C 1  -C 6 )alkyl wherein R 10  and R 11  are each independently selected from the group consisting of hydrogen, (C 1  -C 6 )alkyl, (C 6  -C 10 )aryl(C 1  -C 6 )alkyl and (C 5  -C 9 )heteroaryl(C 1  -C 6 )alkyl; and R 9  is R 12  O or R 12  R 13  N wherein R 12  and R 13  are each independently selected from the group consisting of hydrogen, (C 1  -C 6 )alkyl, (C 6  -C 10 )aryl(C 1  -C 6 )alkyl and (C 5  -C 9 )heteroaryl(C 1  -C 6 )alkyl; and   Ar is (C 1  -C 6 )alkyl, (C 6  -C 10 )aryl, (C 6  -C 10 )aryloxy(C 6  -C 10 )aryl, (C 6  -C 10 )aryl(C 6  -C 10 )aryl, (C 6  -C 10 )aryl(C 6  -C 10 )aryl(C 1  -C 6 )alkyl, (C 6  -C 10 )aryloxy(C 5  -C 9 )heteroaryl, (C 5  -C 9 )heteroaryl, (C 1  -C 6 )alkyl(C 6  -C 10 )aryl, (C 1  -C 6 )alkoxy(C 6  -C 10 )aryl, (C 6  -C 10 )aryl(C 1  -C 6 )alkoxy(C 6  -C 10 )aryl, (C 6  -C 10 )aryl(C 1  -C 6 )alkoxy(C 1  -C 6 )alkyl, (C 5  -C 9 )heteroaryloxy(C 6  -C 10 )aryl, (C 1  -C 6 )alkyl(C 5  -C 9 )heteroaryl, (C 1  -C 6 )alkoxy(C 5  -C 9 )heteroaryl, (C 6  -C 10 )aryl(C 1  -C 6 )alkoxy(C 5  -C 9 )heteroaryl, (C 5  -C 9 )heteroaryloxy(C 5  -C 9 )heteroaryl, (C 6  -C 10 )aryloxy(C 1  -C 6 )alkyl, (C 5  -C 9 )heteroaryloxy(C 1  -C 6 )alkyl, (C 1  -C 6 )alkyl(C 6  -C 10 )aryloxy(C 6  -C 10 )aryl, (C 1  -C 6 )alkyl(C 5  -C 9 )heteroaryloxy(C 6  -C 10 )aryl, (C 1  -C 6 )alkyl(C 6  -C 10 )aryloxy(C 5  -C 9 )heteroaryl, (C 1  -C 6 )alkoxy(C 6  -C 10 )aryloxy(C 6  -C 10 )aryl,(C 1  -C 6 )alkoxy(C 5  -C 9 )heteroaryloxy(C 6  -C 10 )aryl or (C 1  -C 6 )alkoxy(C 6  -C 10 )aryloxy(C 5  -C 9 )heteroaryl wherein each aryl group is optionally substituted by fluoro, chloro, bromo, (C 1  -C 6 )alkyl, (C 1  -C 6 )alkoxy or perfluoro (C 1  -C 3 )alkyl.   
     
     
       2. A compound according to claim 1, wherein n is 2. 
     
     
       3. A compound according to claim 1, wherein X and Y are both CR 1  wherein R 1  is hydrogen. 
     
     
       4. A compound according to claim 1, wherein Ar is (C 1  -C 6 )alkoxy(C 6  -C 10 )aryl, (C 6  -C 10 )aryl(C 1  -C 6 )alkoxy(C 6  -C 10 )aryl, 4-fluorophenoxy(C 6  -C 10 )aryl, 4-fluorobenzyloxy(C 6  -C 10 )aryl or (C 1  -C 6 )alkyl(C 6  -C 10 )aryloxy(C 6  -C 10 )aryl. 
     
     
       5. A compound according to claim 1, wherein n is 2, X and Y are both CR 1  wherein R 1  is hydrogen and Ar is (C 1  -C 6 )alkoxy(C 6  -C 10 )aryl, (C 6  -C 10 )aryl(C 1  -C 6 )alkoxy(C 6  -C 10 )aryl, 4-fluorophenoxy(C 6  -C 10 )aryl, 4-fluorobenzyloxy(C 6  -C 10 )aryl or (C 1  -C 6 )alkyl(C 6  -C 10 )aryloxy(C 6  -C 10 )aryl. 
     
     
       6. A pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, sclertitis, in combination with standard NSAID'S and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier. 
     
     
       7. A method for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of claim 1. 
     
     
       8. A method for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, compounds of formula I may be used in combination with standard NSAID'S and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1, effective in treating such a condition.